US5719054A - Recombinant virus vectors encoding human papillomavirus proteins - Google Patents

Recombinant virus vectors encoding human papillomavirus proteins Download PDF

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US5719054A
US5719054A US08/117,083 US11708393A US5719054A US 5719054 A US5719054 A US 5719054A US 11708393 A US11708393 A US 11708393A US 5719054 A US5719054 A US 5719054A
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virus vector
open reading
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Michael E. Boursnell
Stephen C. Inglis
Alan J. Munro
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Cantab Pharmaceuticals Research Ltd
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
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    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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    • C12P7/00—Preparation of oxygen-containing organic compounds
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
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    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • This invention relates to recombinant virus vectors.
  • it relates to recombinant virus vectors designed to overcome the problem of recombination between homologous nucleotide sequences.
  • It also relates to recombinant virus vectors encoding human papillomavirus proteins; to immunotherapeutics and vaccines for conditions associated with HPV infection; to the production of a virus (e.g. vaccinia virus) engineered to express antigens encoded by human papillomavirus types 16 and 18 and to immunotherapeutics and vaccines for cervical cancer.
  • a virus e.g. vaccinia virus
  • the extent and location of the deleted information within the virus genome is variable, but a general feature is the retention of the part of the genome encoding the E7 protein (Schwarz et al., Nature 314, 111, 1985).
  • the adjacent E6-encoding region is usually present.
  • the ubiquitous presence of the E7-encoding region in tumour cells suggests that the protein product of this gene might play a role in the induction or maintenance of the transformed phenotype. Indeed in most cell lines established from tumour biopsies, expression of the E7 gene can be detected (Smotkin & Wettstein, PNAS, 83, 4680, 1986).
  • the E7 gene product can bind to the retinoblastoma (Rb) gene product, a recognised "anti-oncogene” in normal human cells (Munger et al., EMBO J. 8,4099, 1989). This strengthens the belief that E7 is directly involved in cell transformation.
  • Rb retinoblastoma
  • tumour cells derived from cervical carcinoma biopsies suggest the possibility that these proteins could be potential targets for the immunological recognition of the tumour cells.
  • viral proteins produced inside mammalian cells can be processed through a host cell pathway to short peptides, which then form a complex with host Major Histocompatibility Complex (MHC) Class 1 molecules and are transported to the cell surface. These complexes may then present a target for recognition by the host immune system. Interaction of the complex with the receptor molecule on the surface of cytotoxic T cells (the T cell receptor) can then lead to activation of the T cells to proliferate or to destroy the recognised cell.
  • MHC Major Histocompatibility Complex
  • CTLs cytotoxic T lymphocytes
  • vaccinia viruses containing, and expressing foreign genes
  • Mackett & Smith, J. gen. Virol. 67,2067, 1986 reports of the use of these recombinant viruses to generate effective immune responses against the expressed foreign antigens.
  • a particular advantage of this route for delivery of antigens for vaccination is that it may lead to the development of cellular as well as humoral immunity. This is because the foreign proteins will be produced inside cells of the infected individual in a manner similar to that which occurs during natural infection. This means that they should be processed through the correct pathway to allow generation of a CTL response.
  • tumour-specific antigens such as the human melanoma-associated antigen P97 (Estin et al., PNAS, 85, 1052, 1988), the bovine papillomavirus E7 protein (Meneguzzi et al., Vaccine, 8, 199, 1990) and the human breast cancer-associated antigen ETA (Hareuveni et al., PNAS, 87, 9498, 1990) has been demonstrated to result in the induction of immunity against tumour initiation and progression.
  • human melanoma-associated antigen P97 Estin et al., PNAS, 85, 1052, 1988
  • the bovine papillomavirus E7 protein Melanoma-associated antigen
  • ETA human breast cancer-associated antigen
  • the present applicants have recognised the desirability of producing a recombinant virus vector which is useful as an immunotherapeutic or vaccine for conditions caused by HPV infection, for example for cervical cancer.
  • the art at the time of the applicants making the present invention recognised the E7 gene as having the potential to immortalise cells. Therefore, it would be felt inappropriate to incorporate the E7 gene in an immunotherapeutic.
  • the applicants however, have recognized the surprising usefulness of including the E7 gene in an immunotherapeutic. They have also recognized that the beneficial effects to be gained by treatment with an immunotherapeutic comprising the E7 gene are likely to outweigh by far any risk associated with the oncogenic activity of the E7 gene.
  • an aspect of the applicants invention involves the use of a recombinant virus vector which expresses an E7 gene, as an immunotherapeutic or vaccine. Furthermore, the applicants provide embodiments of their invention in which these risks are reduced still further by specific alteration of the gene sequences in order to reduce the oncogenic potential of the E7 gene without compromising its ability to stimulate an appropriate immune response.
  • HPV proteins which may be encoded by different HPV strains are implicated as being associated with a particular HPV-associated condition (for example, cervical carcinoma, HPV16 and HPV18; genital warts, condyloma acuminata, respiratory papillomatosis, HPV6 and HPV11; squamous cell carcinoma in immunosuppressed individuals, HPV5 and HPV8), rather than produce a plurality of recombinant viruses engineered separately to express each of the implicated proteins, it would be advantageous to produce a single virus recombinant which is able to express part or all of the sequences of more than one of the proteins.
  • HPV-associated condition for example, cervical carcinoma, HPV16 and HPV18; genital warts, condyloma acuminata, respiratory papillomatosis, HPV6 and HPV11; squamous cell carcinoma in immunosuppressed individuals, HPV5 and HPV8
  • the HPV16 E6 and HPV18 E6 proteins show overall homology of 62% and comprise regions of very high homology.
  • HPV16 E7 and HPV18 E7 which show overall homology of 57%, with particular regions of very high homology.
  • the applicants have, however, devised a novel strategy designed to minimise the likelihood of such recombination events and to circumvent the deleterious effect of those events should they indeed arise.
  • the invention provides recombinant virus vectors which comprise at least one pair of nucleotide sequences which have sufficient sequence homology that recombination between them might be expected.
  • the at least one pair of nucleotide sequences may encode part or all of human papillomavirus (HPV) wild-type proteins or mutant proteins immunologically cross-reactive therewith.
  • HPV human papillomavirus
  • the invention provides a recombinant vector which can maintain stably, and express, part or all of four of the desired gene sequences from HPV16 and HPV18.
  • the present invention provides a recombinant virus vector for use as an immunotherapeutic or vaccine which comprises at least one pair of nucleotide sequences heterologous to said virus and which have sufficient sequence homology that recombination between them might be expected wherein said pair of nucleotide sequences are arranged in said virus vector such that they are inverted with respect to each other to reduce the likelihood of recombination events leading to loss of part or all of said sequence and said virus vector is able to infect a mammalian host cell and express as polypeptide the heterologous nucleotide sequences in said host cell.
  • FIG. 1 (Parts a and b): FIG. 1(a) (SEQ ID NOS:7-10) shows the nucleotide sequence and three-frame translation of HPV16 E6/E7 polymerase chain reaction product (underlined regions indicate the E6 and E7 coding sequences); FIG. 1(b) (SEQ ID NO:11-14) shows the nucleotide sequence and three-frame translation of HPV18 E6/E7 polymerase chain reaction product (underlined regions indicate the E6 and E7 coding sequences);
  • FIG. 2 shows the cloning and modification of the HPV16 and HPV18 E6 and E7 Genes
  • FIG. 3 shows an open reading frame plot of vaccinia virus from positions 17201-18450 of the region covered by the four fragments SalF,G,H and I; short vertical lines denote termination codons, lines topped with boxes denote initiation codons, rectangles show relevant open reading frames, and arrows show direction of upper and lower DNA strands;
  • FIG. 4 shows an open reading frame plot of vaccinia virus from positions 21001-22000 of the region covered by the four fragments SalF,G,H and I; short vertical lines denote termination codons, lines topped with boxes denote initiation codons, rectangles show relevant open reading frames and arrows show direction of upper and lower DNA strands;
  • FIG. 5 shows an open reading frame plot of vaccinia virus from positions 23501-25000 of the region covered by the four fragments SalF,G,H and I; short vertical lines denote termination codons, lines topped with boxes denote initiations codons, rectangles show relevant open reading frames and arrows show the direction of upper and lower strands of DNA;
  • FIG. 6 shows a codon usage plot of vaccinia virus from positions 17201-18450 of the region covered by the four fragments SalF,G,H and I; arrows show direction of each DNA strand;
  • FIG. 7 shows a codon usage plot of vaccinia virus from positions 21001-22000 of the region covered by the four fragments SalF,G,H and I; arrows show direction of each DNA strand;
  • FIG. 8 shows a codon usage plot of vaccinia virus from positions 23501-25000 of the region covered by the four fragments SalF,G,H and I; arrows show direction of each DNA strand;
  • FIG. 9 shows the DNA sequence around site A showing translations in single letter amino acid code of genes SalF 17R and SalF 19R;
  • FIG. 10 shows the DNA sequence around site B showing translations in single letter amino acid code of genes SalF 20R and SalF20.5R;
  • FIG. 11 shows a comparison of the SalG2R open reading frame to the yeast guanylate kinase gene sequence
  • FIG. 12 shows the DNA sequence around site D showing translations in single letter amino acid code of genes HindB3R and Hind B4R;
  • FIG. 13 shows the cloning of vaccinia virus (Wyeth strain) neutral sites
  • FIG. 14 shows the cloning of vaccinia virus promoter sequences
  • FIG. 15 shows the construction of vaccinia promoter-driven E6-7 cassette
  • FIG. 16 shows the cloning of the E6-7 cassette into vaccinia virus (Wyeth strain) neutral sites
  • FIG. 17 is a diagram showing the recombination required to generate the final therapeutic vaccinia virus--HPV recombinant virus
  • FIG. 18 shows the synthetic oligonucleotides used in the construction of the therapeutic vaccinia virus HPV recombinant
  • FIGS. 19a and 19b show (SEQ ID NOS:59-62) the nucleotide sequence of vaccinia virus (WR strain) from positions 17201-18450 of the region covered by the four fragments SalF,G,H and I;
  • FIGS. 20a and 20b show (SEQ ID NOS:63-66) the nucleotide sequence of vaccinia virus (WR strain) from positions 21001-22000 of the region covered by the four fragments SalF,G,H and I;
  • FIGS. 21a, 21b and 21c show (SEQ ID NOS:67-70) the nucleotide sequence of vaccinia virus (WR strain) from positions 23501-25000 of the region covered by the four fragments SalF,G,H and I.
  • FIG 22a shows the DNA fragments expected when the HPV DNA cassette is inserted at Site A (as marked on FIGS. 3 and 6) of recombiant vaccinia virus (V9a.1) and FIG. 22b depicts the PCR results;
  • FIG. 23 depicts Western blot analyis for the presence of HPV E67 fusion protein expressed by recombinant virus vector
  • FIG. 24a shows the PCR amplification reaction to confirm presence and arrangment of the inserted HPV sequences and FIG. 24b depicts the PCR results;
  • FIG. 25 shows standard vaccina virus plaque assay results which shows that the recombinant virus retains the ability to replicate mice.
  • FIGS. 26a, 26b, 26c, 26d, 26e, 26f, and 26g show a variety of options for arrangment of HPV16E6 and E7 and HPV18E6 and E7 coding sequences in a recombinant virus vector.
  • the at least one pair of nucleotide sequences may encode part or all of human papillomavirus (HPV) wild-type proteins or mutant proteins immunologically cross-reactive therewith.
  • HPV human papillomavirus
  • the pair of nucleotide sequences may encode part or all of the protein E7 from both HPV16 and HPV18 or functional equivalents thereof.
  • the pair of nucleotide sequences may encode part or all of the proteins E6 from both HPV16 and HPV18 or functional equivalents thereof.
  • the recombinant virus vector may comprise a further pair of nucleotide sequences heterologous to said virus and which (i) have sufficient sequence homology that recombination between them might be expected wherein said further pair of nucleotide sequences are arranged in said virus vector such that they are inverted with respect to each other and said virus vector is able to infect a mammalian host cell and express as polypeptide the further pair of heterologous nucleotide sequences in said host cell.
  • the further pair of nucleotide sequences may encode part or all of HPV wild-type proteins or mutant proteins immunologically cross-reactive therewith.
  • the present invention also provides a recombinant virus vector which in addition to the E7 coding sequences, also comprises and is adapted to express genetic sequences encoding part or all of the protein E6 from both HPV16 and HPV18 or functional equivalents thereof.
  • the genetic sequences may comprise sequences encoding HPV16 E6/E7 and HPV18 E6/E7 as shown in FIGS. 1(a) (SEQ ID NOS:7-10) and 1(b) (SEQ ID NOS:11-14) respectively.
  • the genetic sequences may encode an antigenic moiety of the said proteins.
  • Either or both of the nucleotide sequences in a pair of nucleotide sequences may be altered to make them less homologous than an equivalent pair of nucleotide sequences encoding wild-type HPV proteins.
  • the alteration in nucleotide sequence may be in an area of high sequence homology
  • the alteration in nucleotide sequence will not result in an alteration of the encoded amino acid sequence.
  • Two or more nucleotide sequences each encoding separate proteins may be fused together to form a single open reading frame.
  • the genetic sequences encoding part or all of the proteins E6 and E7 from HPV16 may be fused together to form a single open reading frame.
  • the genetic sequences encoding part or all of the proteins E6 and E7 from HPV18 may be fused together to form a single open reading frame.
  • the genetic sequences encoding part or all of the proteins E6 and E7 from both HPV16 and HPV18 may be fused together to form a single open reading frame.
  • the recombinant virus vector may have the pairs of nucleotide sequences arranged according to any one of the options shown in FIG. 26.
  • the two open reading frames may be inverted with respect to one another.
  • the two open reading frames may be arranged in the recombinant virus vector adjacent to each other. The inversion may be such that the E6 coding sequences of HPV16 and HPV18 are both located between the E7 coding sequences of HPV16 and HPV18.
  • the inversion could be such that the E7 coding sequences of HPV16 and HPV18 are both located between the E6 coding sequences of HPV16 and HPV18.
  • the two open reading frames, each with its respective promoter may be arranged next to each other in the recombinant vector.
  • the promoters may be located between the genes, which are transcribed outwardly, or the promoters may be located outside the genes, which are transcribed inwardly.
  • the genetic sequences encoding part or all of the E7 protein from HPV16 and the E7 protein from HPV18 may be fused together to form a single open reading frame.
  • the genetic sequences encoding part or all of the E6 protein from HPV16 and the E6 protein from HPV18 may be fused together to form a single open reading frame. This leads to another range of arrangements similar to those shown in FIG. 26.
  • the fusions may be via a single codon encoding a relatively small neutral amino acid e.g. glycine.
  • the present invention also provides a recombinant virus vector which comprises a first open reading frame having a fuse genetic sequence encoding part or all of the wild-type proteins E6 and E7 from HPV16; and a separate second open reading frame having a fused genetic sequence encoding part or all of the wild-type proteins E6 and E7 from HPV18; wherein the first and second open reading frames may be inverted with respect to one another whereby either: i) the E6 coding sequences of HPV16 and HPV18 are both located between the E7 coding sequences of HPV16 and HPV18; or ii) the E7 coding sequences of HPV16 and HPV18 are both located between the E6 coding sequences of HPV16 and HPV18; and wherein any of said wild-type proteins may be replaced by a mutant protein immunologically cross-reactive therewith.
  • Each of the first and second open reading frames may have a corresponding promoter and the two open reading frames each with its promoter, are arranged next to each other in the virus.
  • the present invention also provides a recombinant virus vector wherein either: i) the promoters are located between the first and second reading frames whereby the open reading frames are transcribed outwardly; or ii) the promoters are located outside the first and second open reading frames whereby the open reading frames are transcribed inwardly.
  • the present invention also provides a recombinant virus vector which comprises a first open reading frame having a fused genetic sequence encoding part or all of the wild-type proteins E6 and E7 from HPV16; and a separate second open reading frame having a fused genetic sequence encoding part or all of the wild-type proteins E6 and E7 from HPV18; wherein the E6 coding sequences of HPV16 and HPV18 are both located between the E7 coding sequences of HPV16 and HPV18; and each open reading frame has a corresponding promoter, the promoters being located between the first and second open reading frames whereby the open reading frames are transcribed outwardly; and wherein any of said wild-type proteins may be replaced by a mutant protein immunologically cross-reactive therewith.
  • the wild-type proteins HPV16E7 and HPV18E7 may be replaced with mutant proteins which are substantially homologous to said wild-type proteins and in which the residues cys 24 and glu 26 of wild-type protein HPV16E7 and the residues cys 27 and glu 29 of wild-type protein HPV18E7 are replaced with glycine residues.
  • the recombinant virus vector may be derivable from vaccinia virus.
  • the applicants have also recognized that for effective function as an immunotherapeutic, it is desirable for the recombinant virus to retain its ability to replicate and thereby generate an active infection in order that a cellular immune response may be mounted against the virus-encoded proteins.
  • the applicants propose that the foreign gene sequences should be inserted into the vector virus at sites, the disruption of which by the insertion of the heterologous gene sequences will not substantially interfere with, and therefore have a substantially adverse affect on any viral functions which relate to the replicative ability of the virus in the infected host animal.
  • the applicants have named these sites ⁇ neutral sites ⁇ (although the term ⁇ neutral ⁇ should not be interpreted strictly as it is acknowledged that the disruption of these sites may have a small, but relatively speaking inconsequential adverse affect on replicative ability).
  • DNA sequences which affect virus replication can fall into several categories:
  • a non-essential and neutral insertion site must therefore avoid such regions, and, such sites have been identified on the basis of nucleotide sequencing studies.
  • the genetic sequences may be inserted into neutral sites within the virus genome.
  • One or more genetic sequences may be inserted into the same neutral site.
  • Neutral sites can be easily tested for according to techniques well known in the art. For example, a site may be selected, interrupted or deleted using standard methodologies and the resultant recombinant virus placed in conditions which normally support growth of the wild type virus vector, to assess the effect of the manipulations. The pathogenicity of the virus may be further compared with that of the unmodified virus vector strain in animal models, in order to assess its level of attenuation.
  • the virus vector may be vaccinia virus.
  • the vaccinia virus may be attenuated or disabled so that it is unable to fully replicate and establish an extensive infection of host cells.
  • Vaccinia virus has been used extensively in the past for vaccination against smallpox, and its use worldwide has led to the complete eradication of the disease (Bhebehami, Microbiol. Rev., 47, 455, 1983).
  • WHO World Health Organization
  • several different strains of vaccinia virus were used as vaccines.
  • a meeting was sponsored by the WHO to discuss the use of vaccinia virus as live virus vectors (Bulletin of the WHO 63(3): 471-477).
  • the data in this report indicates that the number of complications associated with vaccination was lowest for the Wyeth strain of vaccinia virus, and so this strain has been chosen as a basis for the construction of the recombinant virus according to an embodiment of the present invention.
  • the present invention provides a method for inserting foreign genes at neutral sites within the genome of a virus, the disruption of which sites by the insertion will not interfere with and therefore have a substantially adverse affect on virus replication.
  • the neutral site may be identified herein within the Wyeth strain of vaccinia virus on the basis of the related WR strain nucleotide sequence.
  • sites equivalent to those sites identified above may be used.
  • the neutral sites may be any as identified hereinafter as A (SEQ ID NO:03), B (SEQ ID NO:04), C (SEQ ID NOS:05), and D (SEQ ID NO:06), or a functional equivalent.
  • the recombinant virus vector may comprise a single promoter which controls the expression of all the heterologous genetic sequences within a single open reading frame.
  • the virus may comprise a first promoter which controls the expression of the genetic sequences from a first open reading frame, and one or more further promoters which control the expression of the genetic sequences from one or more further open reading frames.
  • the promoter sequence may be virus--specific and several have been characterised so far (Davison & Moss, J. Mol.
  • the single promoter and the first and one or more further promoters may be the p 7.5 promoter.
  • the single promoter and the first and one or more further promoters may be the p 7.5 promoter.
  • a recombinant virus as provided by the present invention may involve the use of the p7.5 promoter (Venkatesan et al., Cell, 125, 805, 1981) and/or the H6 promoter (Rosel et al., J. Virol, 60, 436, 1988), both of which are active both early and late in infection.
  • the strategy for expression of the protein involves production of E7 as a fusion protein with E6, which is unlikely to retain biological function.
  • Embodiments of the invention provide for reducing this risk still further, by making changes within the E7 gene which are known to destroy its oncogenic capacity (Chesters et al., J. Gen Virol. 71, 449. 1990).
  • the genetic sequences encoding part or all of the E7 proteins may be altered from the equivalent wild type sequences, in order to render the sequences, used in the recombinant virus vectors less oncogenic than their equivalent wild type sequences.
  • the present invention also provides pharmaceuticals comprising recombinant virus vectors as herein defined.
  • the pharmaceutical may be for use against a condition caused by HPV infection which comprises an immunotherapeutically effective amount of a recombinant virus vector.
  • the pharmaceutical may be for use against cervical cancer.
  • the pharmaceutical may be a vaccine to immunise against a condition caused by HPV infection which comprises an amount of recombinant virus vector as herein provided which when administered to a recipient can specifically activate cells of the immune system to HPV proteins.
  • the vaccine may be for immunisation against cervical cancer.
  • the pharmaceuticals may comprise one or more excipients.
  • the present invention also provides methods of using the recombinant virus vectors as herein defined to make medicaments for use as immunotherapeutics or vaccines against conditions thought to be caused by HPV infection. For example for the prophylaxis and treatment of cervical cancer.
  • the present invention also provides methods of treating mammalian patients with recombinant virus vectors and pharmaceuticals as herein provided.
  • the present invention also provides a method of determining a neutral site in a virus vector, the disruption of which by the insertion of heterologous gene sequences will not interfere with, and therefore, have a substantially adverse affect on viral function which relates to the replicative ability of the virus.
  • the method for this determination comprises: (a) analysing a viral genome to identify open reading frames which are likely to encode functional genes, by looking for expected codon usage between spaced apart start and stop codons; and (b) selecting sites which are not in such open reading frames, likely to encode functional genes, as identified in (a) This may include selecting sites between open reading frames for sequences of functional genes and selecting sites which are in open reading frames which have some functional gene characteristics, such as an expected codon usage, but have lost other essential characteristics such as a start codon.
  • the method may also comprise interrupting or deleting the selected sites from the viral genome and placing the resultant virus in conditions which normally support growth of the wild type virus.
  • the present invention also provides neutral sites identified by use of the above methods.
  • the present invention provides an embodiment which shows a way of inducing a cellular immune response against the papillomavirus proteins usually expressed in cervical tumour cells by the creation of a recombinant vaccinia virus, which has been engineered to produce the HPV E6 and E7 proteins, or proteins containing HPV E6 and E7 sequences, during its replication cycle.
  • This therapeutic vaccinia virus contains the E6 and E7 genes from both HPV16 and HPV18, the viruses most commonly associated with cervical carcinoma. Vaccination with this single virus may thus stimulate immunity to the E6 and E7 proteins of the HPV types associated with more than 80% of cervical tumours. Expression of all four gene sequences (e.g.
  • HPV16 E6 and E7; HPV18 E6 and E7) in a single virus however presents a problem, because of the likelihood of loss of genetic sequences through recombination.
  • the present invention provides a method for circumventing this difficulty, firstly through specific sequence alteration, in order to reduce sequence homology and secondly through their insertion into the vaccinia virus genome in such a way that if such recombination were to occur, it would not lead to loss of sequences (i.e. in inverted orientation with respect to each other).
  • Expression of the desired four gene sequences in the vaccinia virus genome could also be difficult (though not impossible) to achieve as independent expression units, and so the invention provides that instead, the E6 and E7 open reading frames may be fused together.
  • a problem with standard methods for insertion of foreign information into the vaccinia virus genome is that the use of selectable markers to increase the efficiency of recombination results in the ultimate presence in the recombinant virus also of the selectable marker gene itself.
  • Methods for insertion have been developed however, which allow subsequent elimination of these extraneous sequences (Falkner & Moss J. Virol., 64, 3108, 1990) and these are used in an embodiment of the present invention to ensure that the final recombinant vaccinia virus has only those additional sequences which are necessary for its required function.
  • a fragment of DNA containing the HPV16 E6/7 coding region is prepared by polymerase chain reaction (PCR) amplification from the plasmid pBR322/HPV16 (Durst et al., PNAS, 80, 3812, 1983) using the oligonucleotides SO5 and SO6.
  • a fragment containing the same region from HPV18 is prepared by the same procedure from plasmid pBR322/HPV16 (Boshart et al., EMBO J. 3,1151) using the oligonucleotides SO1 and S02.
  • Plasmids pBR322/HPV16 and pBR322/HPV18 are both available from Behringwerke AG, P.O. Box 1140 D-3550, Marburg, Germany (alternatively the necessary sequences can be created synthetically from the sequence information provided by the present application).
  • this produces a DNA fragment of about 800 base pairs (bp) with a site for the restriction enzyme Nco 1 (CCATGG) located exactly at the beginning of the E6 gene, and a Smal site immediately downstream of the termination codon for the E7 gene (FIGS. 1(a) and (b)).
  • CCATGG restriction enzyme Nco 1
  • Ncol-Smal digested plasmid pUC118NS (a modified version of the "phagemid" pUC118 (Viera & Messing, Methods Enzymol., 153,3, 1987) in which Ncol and Smal sites have been created by site-directed mutagenesis within the poly-linker region) to generate the plasmid p1MS7, containing the HPV16 sequences, and pIMS8 containing the HPV18 sequences (FIG. 2).
  • the use of pUC118 is not crucial to the present strategy as any plasmid which can be manipulated by site directed mutagenesis can be successfully used.
  • the E6 and E7 genes from each HPV type are first fused together to form a single continuous ORF. This is achieved by site-directed mutagenesis as follows:
  • the invention provides ways of minimising this risk. Firstly, by inserting the two sets of genetic information in the vaccinia genome in opposite orientation to each other (so that recombination will result not in the loss of sequence information, but rather in its inversion). Secondly, by creating specific changes in the E6/7 sequence of one of the HPV virus strains at sites where the homology is greatest. These changes however are made in such a way that the amino acid coding potential of the genes remains unaltered.
  • HPV18 E6 sequences is therefore altered by site-directed mutagenesis as follows:
  • TTTTTATTCTAGAATTAGAG (SEQ ID NO:01) (which begins 210 nucleotides from the start of E6--underlined in FIG. 1(b)) is mutated, using oligonucleotide S24 to the sequence TTTCTACAGTAGAATCAGAG (SEQ ID NO:02)(pIMS8.2--FIG. 2) (changed nucleotides are in bold type).
  • a second aim of this change is to eliminate from the HPV18 E6 sequence, the sequence TTTTTAT, which is a potential termination signal for the early vaccinia virus transcription enzyme (Rohrmann et al., Cell., 46, 1029, 1986).
  • the Wyeth strain of vaccinia virus is used for construction of the therapeutic virus. It is propagated in Vero cells for the purposes of genetic manipulation, and in the human diploid fibroblast cell line MRC5 for the production of the final therapeutic virus stock. Both cell lines are obtained from the National Institute of Biological Standards and Control, South Mims, U.K.
  • the Wyeth strain of vaccinia virus, Vero cells and the cell line MRC5 are also available from the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A.
  • sites For the purpose of insertion of papillomavirus genes within the vaccinia virus genome, sites have been chosen to have two characteristics.
  • TK thymidine kinase
  • Site C in SalG2R, a potential non-functional gene
  • Site D in HindB3.5R, a potential non-functional gene
  • These sites (A-D) can be identified by the following stretches of DNA sequence, each of which is 40 nucleotides in length.
  • sequences may vary, while still having substantial homology with those given above.
  • a site may have at least 90%, more preferably 95%, homology with the sequence given above.
  • FIGS. 3-5 show the distribution of initiation codons and open reading frames (ORFs) in the regions of the vaccinia virus genome shown in FIGS. 19, 20 and 21.
  • FIGS. 6-8 show the same regions with a plot showing to what extent each reading frame conforms to the pattern of codon usage expected for vaccinia genes.
  • a graph of codon usage is plotted for each of the three possible reading frames in each direction (Staden, R., Nucl. Acids Res., 12, 521, 1984; Staden, R., Nucl. Acids Res., 12, 551, 1984).
  • the short vertical bar lines extending from the horizontal axes represent start codons.
  • the longer vertical bar lines placed above the horizontal axes represent stop codons. This sort of plot is a useful way of helping to determine whether a particular ORF is a genuine vaccinia gene.
  • the graph of codon usage will rise between a start codon and a stop codon.
  • the graph of codon usage rises over the region of the SalG2R ORF (the dotted line shows that this frame conforms most of the expected codon usage).
  • the graphs show that they do not conform to vaccinia codon usage.
  • the peak labelled ⁇ part of gk ⁇ , and marked with a dashed line, also conforms well to vaccinia codon usage.
  • a genuine gene must start with an initiation (start) codon, end with a termination (stop) codon, and should conform well to vaccinia codon usage along its length. In most cases the conformation to the vaccinia codon usage drops off sharply outside the gene.
  • the neutral sites are further described as follows
  • FIG. 9 shows the actual DNA sequence with a translation of the ORFs on either side of the site. It can be seen that Site A is placed in an intergenic region between SalF17R and SalF19R. It is placed some 195 bases upstream of SalF19R to avoid any promoter elements associated with that gene.
  • the sequence TTTTTCT (shown in italics) will act as a terminator of early RNA transcription for the SalF17R gene if it is an early gene. However, the site is placed downstream of the first of these, so it will not affect early termination of transcription if it occurs. Examination of FIG. 6 shows that there is no recognisable gene on the opposite strand at this point, and hence this sequence location is suitable as a neutral insertion site.
  • FIG. 10 shows the actual DNA sequence with a translation of the ORFs on either side of the site. It can be seen that Site B is placed in an intergenic region between SalF19R and SalF20.5R.
  • FIG. 6 shows that it is within a region of high vaccinia codon usage, but that this region does not form a genuine gene, having no initiation codon.
  • FIG. 6 suggests that Sal20.5R is not a complete gene, as the conformation to vaccinia codon usage drops off dramatically at the start of the gene.
  • SalF20.5R is a genuine gene
  • Site B is placed some 70 bases upstream of SalF20.5R which may well avoid any promoter elements associated with that gene. (Note: many vaccinia promoter elements are located in approximately 35 bases upstream of the start of the gene.)
  • the SalG2R gene is not active as a guanylate kinase and can be referred to as a ⁇ pseudogene ⁇ . If the gene is inactive as the applicants deduce, then it will serve as a neutral insertion site.
  • FIG. 5 shows that site D lies within the region designated HindB3.5R.
  • This region although conforming to vaccinia codon usage, has no start codon and is therefore not a genuine gene.
  • the codon usage plot shown in FIG. 8 indicates that it probably was once a functional gene, and may well have been attached to HindB3R (a shift in the codon usage preference occurs here well away from the termination codon of the HindB3R ORF which suggests that the last section of HindB3R is not properly part of this gene.)
  • HindB3.5R is not active as a gene and can be used as a neutral insertion site.
  • FIG. 12 shows the actual DNA sequence with a translation of the ORFs on either side of the site. It can be seen that site D is placed in an intergenic region between HindB3R and HindB4R as well as being within the non-functional HindB3.5R.
  • DNA copies of the neutral sites together with an appropriate amount of flanking DNA from the vaccinia genome (approximately 500 bases on either side) must first be cloned into a plasmid vector.
  • These plasmids may then be used to introduce the foreign DNA into the vaccinia virus genome; the vaccinia virus ⁇ flanking sequences ⁇ around the inserted gene serve to allow homologous recombination between the plasmid DNA and the viral DNA, with the consequent insertion of the foreign gene at the desired location.
  • Plasmids containing flanking regions from the neutral sites are constructed as follows.
  • DNA is prepared from the Wyeth strain of vaccinia virus by the method of Esposito et al., (J. Virol. Meth. 2: 175, 1981).
  • the polymerase chain reaction (PCR) is used to remove an approximately 1000 base pair (bp) fragment from DNA of the Wyeth strain of vaccinia virus.
  • Pairs of oligonucleotides are chosen approximately 500 bp either side of the chosen neutral site. These oligonucleotides are based on the sequence of the WR strain, but are chosen in regions where the sequence of the WR strain is identical to that of the Copenhagen strain (Goebel et al., Virology 179:247, 1990).
  • the oligonucleotides incorporate restriction enzyme recognition sequences so that they can be cloned easily into a plasmid.
  • restriction enzyme recognition sequences For neutral sites A (SEQ ID NO:03), B (SEQ ID NO:04), and D (SEQ ID NO:06) the restriction sites are EcoR1 and HindIII.
  • neutral site C SEQ ID NO:05
  • the HindIII site is replaced by an Sphl site, since there is an internal HindIII site in the chosen flanking sequences.
  • oligonucleotides used for PCR are listed below:
  • DNA fragments of approximately lkb are then prepared using these pairs of oligonucleotides by PCR amplification, digested with EcoRI and HindIII (for site A (SEQ NO:03), B (SEQ ID NO:04) and D (SEQ ID NO:06) or with EcoRI and Sphl (for site C (SEQ ID NO:05)) and cloned into HindIII and EcoRI-digested pUC118 (FIG. 13) to generate the plasmids pIMMC7a, pIMMC7b, pIMMC7c and pIMMC7d.
  • a suitable restriction enzyme site is then introduced at the selected location within each of the plasmids. This is achieved using site directed mutagenesis using an oligonucleotide containing the desired new unique site and flanked by 15 bases of sequence to either side (see below).
  • the plasmids modified in this fashion are designated pIMMC8a-d (FIG. 13).
  • the p7.5 and H6 promoters from vaccinia virus genomic DNA are prepared by PCR amplification as described below.
  • a pair of complementary oligonucleotides (S7 and S8) is synthesised to include the following restriction enzyme sites, HindIII, Snal Hpal, HindIII, Sall, Ncol, Smal, SnaBl and EcoRl such that the pair, after annealing, present at one end HindIII compatible overhanging ends, and at the other, EcoRl compatible overhanging ends.
  • the two oligonucleotides are allowed to anneal and are inserted into pUC118 cut with EcoRl and HindIII (FIG. 14).
  • the resulting vector is called pIMMC3.
  • a DNA molecule of approximately 180 bp containing the H6 promoter is removed from the WR strain of vaccinia virus by PCR amplification using the oligonucleotides MB15 (anneals upstream and includes a 5'-Sall site) and MB7 (anneals downstream and includes a 5'-HindIII site). This is cloned into pIMMC3 cleaved with HindIII and Sall to create pIMMC4a (FIG. 14).
  • a DNA molecule of approximately 200 bp containing the p7.5 promoter is then removed from the WR strain of vaccinia virus by PCR amplification using the oligonucleotides MB32 (anneals upstream and includes a 5'-Sall site) and MB33 (anneals downstream and includes a 5'Ncol site). This is cloned into pIMMC3 cleaved with Ncol and Sall to create pIMMC14b.
  • the strategy required to generate a recombinant vaccinia virus containing and expressing the E6-E7 proteins from HPV16 and HPV18, based on the elements described above involves five main stages as outlined below.
  • a DNA fragment containing the modified HPV16 E6-7 sequence is excised from pIMS7.2 by digestion with HindIII and Smal, and cloned into HindIII and Hpal-digested pIMMC4a to generate pIMS12 (FIG. 15).
  • a DNA fragment containing the modified HPV18 E6-7 sequence is excised from pIMS8.2 by digestion with Ncol and Smal, and cloned into Ncol and Smal-digested pIMMC14b to generate pIMS14 (FIG. 15).
  • a DNA fragment containing the HPV18 E6-7 region together with the upstream p7.5 promoter is excised from pIMS14 with Sall and Smal and inserted into Sall and Smal-digested pIMS12 to generate pIMS15 (FIG. 15)
  • a DNA fragment containing both the HPV16 and HPV18 E6-7 coding regions together with their upstream promoter elements is excised from pIMS15 with SnaB1 and inserted into the appropriately-digested neutral site-containing plasmids pIMMC7a-d. This step is shown in FIG. 16, and the resulting plasmids are designated pIMMC9a-d.
  • vaccinia The recombinant plasmids pIMMC9a-d are purified and allowed to recombine into vaccinia (FIG. 17) using standard protocols (Mackett et al., in D. M. Glover (ed) DNA Cloning: a Practical Approach, Oxford and Washington D.C., IRL Press, 1985). Viruses which have acquired the HPV sequences are identified by probing with radiolabelled HPV specific sequences. Viral plaques are lifted onto nitrocellulose (Villareal and Berg, Science 196, 183, 1977) and probed with radiolabelled NcoI-SmaI fragment from pIMS14 containing the HPV18 E67 gene. Recombinant viruses are then isolated from the agarose overlay and plaque purified three times.
  • Stocks of the final recombinant virus are prepared by growth in Vero cells, and are used to infect MRC5 cells deemed suitable for the preparation of material suitable for use as human vaccines.
  • the virus is plaque-purified three times by standard methods, and finally a stock prepared for clinical use.
  • FIG. 22 shows the analysis by PCR, of a recombinant vaccinia virus (v9a.1) in which the HPV DNA cassette is inserted at Site A.
  • the diagram shown in panel (a) indicates the DNA fragments expected if insertion of the correct DNA has occurred. It can be seen in panel (b) that the actual pattern of PCR products generated is consistent with that expected.
  • the recombinant viruses are then checked for expression of the expected HPV proteins.
  • An example of this analysis is shown in FIG. 23.
  • Vero cells are infected with recombinant virus v9a.1 (HPV DNA inserted at Site A), and the cells examined by western blotting for the presence of the HPV E67 fusions proteins using monoclonal antibodies specific for the HPV16 E7 protein (camvir3) and for the HPV18 E7 protein (7E10). It can be seen that both monoclonal antibodies recognise specifically proteins of the expected size in cells infected with the recombinant virus v9a.1, but not in cells infected with the control parent virus Wyeth strain.
  • the recombinant virus For the recombinant virus to be of use clinically, it is important that the inserted sequences remain genetically stable over multiple virus passage, and the DNA insert was carefully designed to promote this genetic instability.
  • the virulence of the recombinant virus is compared in animal experiments with that of the parental Wyeth strain.
  • Groups of 20 mice are inoculated intranasally each with 10 7 pfu of Wyeth strain or recombinant virus in a total volume of 20 ⁇ l .
  • Two mice are sacrificed at 1 day, 3 days and 5 days following inoculation, and the lungs dissected out.
  • the amount of virus present in the lungs is then measured by grinding the tissue, and assay of the homogenate by standard vaccinia virus plaque assay.
  • the results of such an experiment for the recombinant virus v9a.1 HPV infromation inserted at site A (SEQ ID NO:03) are shown in FIG. 25. It can be seen that the recombinant virus retains the ability to replicate in mice, and that the level of virus produced in the lungs of the infected animals is similar to that seen with the parental Wyeth strain.
  • a stock of the recombinant virus is prepared by infection of MRC5 cells, and adjusted to a concentration of not less than 10 8 pfu/ml. 20 ⁇ l of this material is applied to the arm of the patient, which is then scarified through the virus droplet with a bifurcated needle, according to the standard procedure used for vaccination against smallpox.

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